An important triazolopyrimidine compound is ticagrelor (TCG; Brilinta®; 3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-(1S,2S,3R,5S)-1,2-cyclopentanediol) having the following structural formula.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation (WO 00/34283).
The synthesis of ticagrelor (TCG) is demanding. There are five to six known synthetic variants, which are described in the basic patent application WO 00/34283, an improved one in patent application WO 01/92263, and a further improved one in patent application WO 10/030,224 respectively derived from the originator AstraZeneca, while two are published in a “deutero” patent application WO 11/017,108 of Auspex Pharmaceuticals. Further, there is one synthetic path published in a scientific journal (Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018).
The first synthesis of TCG as described in WO 00/34283 is depicted in scheme 1 below.

This nine step synthesis of ticagrelor (TCG) as described in WO 00/34283 (Scheme 1) starts with a reaction between CLIN and AMAL. In the presence of diizopropylethylamine (iPr2Net) AMALCIN is formed, which is in then reduced with iron (Fe) in acetic acid to AMALCINA. In the next step CLTAM is formed using isopentyl nitrite (iAmONO). Next, ATAM was prepared using ammonia, and side chain was introduced (MATAM) using n-butyllithium and methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate, which was previously prepared by reaction between methyl glycolate and triflic anhydride. In next step BRTAME is formed using iAmONO and CHBr3, followed by the aromatic nucleophilic substitution of Br with CPA in the presence of iPr2NEt to form CPATAME. This is than reduced to CPATAMA using DIBAL-H. Deprotection of diol group in the presence of trifluoroacetic acid in the final step leads to TCG. This synthetic path is very long (9 steps, not including reagents preparation) and uses toxic compounds like CHBr3, triflic anhydride, and methyl 2-(((trifluoromethyl)sulfonyl)oxy)acetate.
An improved synthesis of ticagrelor (TCG) is described in WO 01/92263 (see Scheme 2). In this process the hydroxyethyl side chain is introduced at the beginning of the synthesis by a three step reaction path from AMAL to AMALA, which is then reacted with CLINA (prepared from CLIDA) in presence of triethylamine (Et3N) to form AMALCINAA. The triazole ring of CLTAM is formed with NaNO2 in acetic acid, and then Cl is exchanged with CPA to form CPATAMA. In the final step TCG is prepared via deprotection using NCl.
This improved process still has substantial length (7-8 steps). In AMALA synthesis the benzyloxycarbonyl protection (Cbz) is used, which is then removed in the third step using hydrogenation with Pd/C as a catalyst. Also, hydrogenation with Pt/C as a catalyst is used in the reduction of CLIDA to CLINA.

Another improved synthetic path is described in WO 10/030,224 (Scheme 3). The key steps in this process are reduction of CLIN to CLINA or AMALCINO to AMALCINAA using hydrogen gas and platinum vanadium catalyst. The introduction of the hydroxyethyl side chain to AMAL to form AMALA, cyclization, substitution of Cl atom of CLTAMA with CPA and final acidic deprotection are the same as in WO 01/92263.
This further improved process to TCG has 8 reaction steps. Like in WO 01/92263, there are used the Cbz protecting group and heavy metals as catalysts like Pd, Pt and/or V.

AstraZeneca published a synthetic path (Scheme 4) to ticagrelor (TCG) in Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018. Intermediates in this process are similar to those described in WO 01/92263. There is difference in formation of triazolo ring of CLTAMA where iAmONO is used, and difference in deprotection in the last step.

Another synthetic variant (Scheme 5) to ticagrelor (TCG) is described in WO 11/017,108 by Auspex Pharmaceuticals. In nine step synthesis they prepared AMALE through deprotection of ZAMALE using hydrogen gas and Pd/C, which was then reduced to AMALA with LiAlH4. AMALCINO was prepared without presence of base, further steps are similar to those published in WO 01/92263.
Still another synthetic variant (Scheme 6) to obtain ticagrelor with deuterated hydroxyethyl group (TCGD) is also described in WO 11/017,108 by Auspex Pharmaceuticals.


O-alkylation of the secondary alcohol functional group is often a demanding step for which a strong base such as sodium hydride is needed. The chemoselectivity problem arises in the presence of the reactive heteroaryl chloride functionality, because the oxy anion formed may attack the position of chloro atom (“selfarylation”) leading to considerable amounts of by-products (Scheme 7). In the known procedure, published in WO 00/34283 and represented in Scheme 1 the unwanted side reaction is avoided by first changing the reactive halogen to amino group, than conducting alkylation step and finally converting amino group back to halo group.
Alternatively, hydroxyethyl group can be introduced by alkylation of cyclopentane part before heteroarylation as presented in upper parts of Schemes 2 to 6. However, in order to alkylate hydroxy group in the presence of an amino group the nitrogen atom must be protected.

As becomes apparent from the above, a major drawback of the hitherto known synthesis schemes for the preparation of ticagrelor is that the synthesis is long.